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PHGY 312 > Respiratory #8- > Flashcards

Respiratory #8- Flashcards

1
Q

In what situations are persons exposed to hypoxic conditions?

A
  • High altitude
  • Breath-holding (free diving)
  • Disease causing arterial hypoxemia (ex: sleep apnea)
  • Poisoning (cyanide, CO) → poison you mitochondria
  • Profound anemia
  • Shock (circulatory collapse)
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2
Q

What is the difference between hypoxia and hypoxemia?

A

Hypoxia = shortage of O2 delivery to the tissues
Hypoxemia = arterial blood O2 level are abnormally low, tissues are not necessarily affected

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3
Q

Which cells are responsible for initiating neural activity in carotid bodies?

A

Type I cells = gloma cells → sense changes in environment → release neurotrasmitters → IX afferent cranial nerve (Glossopharyngeal nerve) → brings the stimulation to the brain stem (pons, respiratory center, medulla)

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4
Q

What are the different cellsand receptors in the carotid body?

A

Type 1 cells → gloma cells
Type 2 cells → release mediators onto gloma cells (via synapses) → influence activity of gloma cells → activating sensory neurons
Progenitor cells → give rise to the new gloma cells
P2YR → G-protein coupled receptors
P2XR → Ion channel

*Exposure to chronic hypoxia → increase in gloma cells → growth of carotid bodies (Hyperplasia)

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5
Q

What substances are responsible for modulating gloma cell function?

A

ATP + adenosine → excitatory (released by Type II cells)

Dopamine → inhibitory
Opioids → inhibitory

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6
Q

What mechanisms allow oxygen sensing in the gloma cells?

A

Oxygen sensing = result of events in the mitochondria:
1. Reduction in PO2 in the region of the mitochondria → less ATP produced → production of lactate (glycolysis to replace oxidative phosphorylation) and ROS within the mitochondria → inhibition of K+ channels

  1. Decrease in PO2 activates HO-2 (hemeoxygenase-2 enzyme) → production of CO → inhibition of K+ channel

Inhibition K+ channel → depolarization → Ca++ influx → neurotransmitter release
*If depletion of Ca2+ → not hypoxic response

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7
Q

What are different stimulus the glumus cells respond to?

A
  • Hypercapnia
  • Acidemia
  • Hypoxia
  • Lactate
  • Hypoglycemia
    Other stimulus → Leptin, insulin, temperature, osmolarity, reduced blood flow
    *At lower pH, electrical activity is increased

*Gloma cells spike in these environment

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8
Q

How can we artificially stimulate Gloma cells?

A
  • Expose them to hypoxic environment (spikes only if there is calcium, if deplete → stop the response)
  • Expose them to NADPH (more H+ ions)
  • Expose them to ∆ROS

*Normally there is a balance in NAD, NADP and NADH, NADPH

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9
Q

What are the effects of stimulation of chemoreceptors?

A
  • Increase in phrenic nerve activity and ventilation
  • Sympatho-excitation
  • Tachycardia or Bradycardia
  • Endocrine
  • Cardiac (more flow/venous return/vasodialation/contractility)
  • Gastrointestinal (
  • Metabolic (decrease sympathetic activity)
  • Increase hematocrit
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10
Q

What stimulation is necessary for tachycardia to occur?

A

Occurs when stimulation of carotid bodies + hyperventilation

If hyperventilation, can’t occur (ex: during sleep apnea → airways are blocked) → sympathetic activation → increase in blood pressure
parasympathetic → bradycardiac response to chemoreceptor stimulation

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11
Q

What is the effect of hypoxia on blood vessels?

A

V/Q is adjusted to ventilation:
Adjusted of perfusion to areas where there is less ventilation
Some pulmonary arteries constrict to ensure the blood is not distributed uselessly to not ventilated area → more constriction → more resistance of pulmonary circulation → Pulmonary hypertension (high BP within pulmonary circulation)
*Effect of hypoxia on blood vessels

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12
Q

What are different gene product associated with pulmonary arterial hypertension?

A

*Via smooth muscle cells within pulmonary arteries

Endothelin → contraction
TRPC1, TRPC6 Transient receptor potential Ca2+ channel → allow calcium influx → favour contraction (whole family of these that can sense changes in osmolarity, etc.)

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13
Q

What is the effect of continuous vs intermittent hypoxia on HIF?

A

Continous: Upregulation of HIF-1a and HIF-2a in pulmonary arterial smooth muscle cells → pulmonary hypertension + hypertrophy (increase in size of muscle cells) + hyperplasia (increase in number of muscle cells)

Intermittent: upregulate HIF-1a and down regulated HIF-2a in the carotid body → systemic hypertension

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14
Q

What is the role of mitochondria in the pulmonary artery?

A

Sensors for Oxygen

Normoxia → favour production of NAD over NADH, H+ ions move into inter-membrane space → diffuse back through ATP-synthase channel
also have O2- → H2O2 → degraded by catalase

Hypoxia → more NADH present, defficiency of H+ ions gradient → decline in membrane potential → les production of ATP, more O2- produced under hypoxia

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15
Q

Explain the oxidized and reduced redox balances and their effect on ion channels?

A

Oxidative redox balance → balance of NAD+/NADH (favour NAD+), more H2O2, funcitonal K+ channels → keep membrane gradient, Ca2+ no flowing

Reduced redox balance = fall in ATP → decrease NAD+/NADH balance (favour NADH), reduced HO2, K+ channels are blocked → Ca2+ influx (into cytosol) → contraction of smooth muscles

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16
Q

What experiment allowed analysis of hypoxia detection by looking at TRPA1 channels?

A

EXPERIMENT 1:
1. Mice put in chamber (exposed to hypoxi (15% or 10%) a or room air (21%)) → choice of which chamber to be in
2. Measure time spent in hypoxic chamber → TRPA1 KO mice spent more time than KO in hypoxic chamber
If exposed to 10% → stimulus is strong enough that none of the mice stayed in hypoxic chamber

EXPERIMENT 2:
- Expose to ramp of hypoxia
- Mice have EEG → tell if asleep or awake
Looked to see when they woke up → WT mice had much reduced time for arousal, KO mice did not (wtill very slow to wake up and woke up at lower %O2)

*TRPA1 present in dorsal route ganglia → Xth cranial nerve, no evidence in carotid body → completely different mechanism of detecting hypoxia

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17
Q

How is hypoxia related to Erythropoietin?

A

Hypoxia → synthesis of erythropoietin
EPO produced in kidney (a bit in the liver)

Hypoxia → inhibition of HIF-PHD → HIF-2a is not degraded → translocated to nucleus → trigger production of EPO → increased hematocrit
*More fetal Hb is synthesized with higher O2 affinity

EPO stimulates bone marrow → produce RBC

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18
Q

How does HIF degradation occur? Why is it important?

A

It limits production of EPO

Normally HIF-2a associated with VHL (Vin Hippel-Lindau protein) → Proline hydroxylase maintain the links between HIF and VHL → HIF-2a degraded in the proteasome (Rapid HIF turnover)

PHD uses O2 to dissociate the complex → inhibits HIF-2a degradation → transcription of several factors

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19
Q

How does sleep affect CO2 responses?

A

Sleep depresses response to CO2 → CO2 rises during sleep (At same minute ventilation, PCO2 is higher during sleep)

20
Q

What is obstructive sleep apnea?
What do recordings look like?

A
  • Brief occlusion of the upper airways during sleep → associated with hypoventilation and hypercapnia
  • Common condition associated with obesity

Can cause daytime fatigue, sleepiness, memory loss, poor concentration, some can suffer from daytime hypercapnia (chronical elevated CO2)
- Involves cardiovascular and respiratory responses

Recordings:
EMG → bradycardia
Hyperventilation when there is release of obstruction
During obstruction → decline in O2 and O2 saturation
If there is still a little flow (not straight line) → hypercapnia, not apnea
*Person often wakes up very often without realizing

21
Q

What is the difference between central apnea and obstructive apnea?

A

Central apnea → No drive to breathe / no respiratory muscle activity (no change in esophageal pressure)
*Straight line in esophageal pressure

Obstructive apnea → struggle to open airways → gradual increase in negative pleural pressure / increase in drive to breathe → person wakes up → release obstruction (associated with decrease in O2 saturation)
*Increase oscillation in esophageal pressure (goes to more negative)

22
Q

What is the effect of breath-hold on arterial PO2 and CO2?

A

PO2 gradually decreases → not too bad because still in the flat part of Hb curve (saturation stays about the same)
PCO2 gradually increases → involuntary contraction of diaphragm, urgency to breathe arises

23
Q

What do the different lines detect in a normal polysomnogarph ?

A

Polysomnograph → When person sleeps

EEG → brain action
EMG → occular muscle movement
ECG → HR response
BP → Blood pressure
Movement of chest and abdomen
Tidal volume → can be determined by looking at abdominal and chest excursion

24
Q

How can PiO2 be calculated from barometric pressure? (Oxygen concentration at altitude)

A

Pinspired O2 = FiO2 * P barometric
PiO2 = 20.9 * Pb

At sea level, Pb = 760 mm Hg
Fractional concentration = 20.9%

25
Q

How is the change in PO2 between different compartements of the respiratory system affected by altitude?

A

Inspired gas → Alveolar gas: at high and low altitude, same decrease in PO2 (addition of water vapour and CO2 so based on Dalton law partial pressure changed, not O2 content)
Alveolar gas → Arterial blood: at high and low altitude, very small dip in PO2 as you get small anatomical and physiological shunts (a bit more at sea level)
Arterial blood → mixed venous blood: Much bigger decrease in PO2 at low altitude, at higher altitude lower general PO2 → less gradient → less diffusion force/less O2 to extract

*At high altitude, start with much lower Pinsp. O2 (~80 mm Hg at 4600m instead of 150 mm Hg at sea level)
*2 Curves convert at the level of the mixed venous blood, both ~ 40 mm Hg (a bit lower at high altitude)

26
Q

What is the difference at altitude vs sea level for end-capillary equilibration of PO2?

A

At sea level, equilibration happens very fast (0.3 sec) → end-capillary = alveolar PO2
At high altitude, slow equilibration/very gradual rise because smaller gradient → transit time for blood might be to short for equilibration to be achieved, worst if exercise
*PO2 starts at mixed venous blood PO2

27
Q

What is the relationship between VO2max (ability to consume oxygen) and altitude?

A

Plateau closer to sea level and VO2 decreases faster as you get to higher altitudes (exponential curve the other way/curvilinear relationship)
VO2 = 100% at 760 mm Hg
VO2 = 40% at ~ 320 mm Hg ~ 6000m

Diminished exercise capacity for permanent residents or visitors (compared to sea level)

28
Q

What is the importance of alveolar hyperventilation at extreme altitude?

A

Alveolar hyperventilation is essential for survival at extreme altitudes
PaO2 = PiO2 - (PaCO2/R) = 150 - (40/0.8) = 100 at sea level
At top of mount everest → PaO2 = 43 - (40/0.8) = -7 …
Need to reduce PaCO2 by massive hyperventilation to have enough PaO2 (when get rid of CO2, can accomodate more O2)

R ~ 0.8 normally, ~ 1 if only metabolizing carbs, ~0.7 if only metabolizing fat

29
Q

What is a bad side-effect of necessary hyperventilation at high altitudes? (brain)

A

Hypocapnia has effects on cerebral blood flow (much reduced)
Normocapnia ~ 35-40 mm Hg

Chicken, ducks, goose → not much change in cerebral blood flow at lower CO2 which allows them to fly at very high altitude (will still hyperventilating)

30
Q

How does alveolar ventilation adapt to altitude?

A

With hyperventilation at altitude → alveolar CO2 goes down
With lower PCO2 → higher pH in CSF (alkalosis) → counter act effect of stimulation of ventilation

Lower PCO2 → less chemoreceptor input at central and peripheral receptors
Overtime (days/weeks) → kidneys will reduce bicarbonate production → less bicarbonate in the blood → less buffer for H+ → lower pH → CSF adjusts → ventilatory response to hypoxia is enhanced (not as reduced because of lower PCO2)
*Higher ventilatory drive in response to hypoxia for visitors if they stay a bit longer

31
Q

How does hypoxic ventilatory drive change for low altitude natives vs high altitude native?

A

Hypoxic ventilatory drive is much higher for low altitude natives than high altitude natives (linear relationship → decreases as spend more years at altitude)
(NOT what is seen as visitors show an increase in hypoxic ventilatory drive overtime)

32
Q

What explains periodic breathing at high altitude?

A

Periods of excessive ventilation → central apnea → excessive ventilation → central apnea, etc.

*Central apnea as respiratory muscles are not innervated during periods of apnea (apnea = cessation of airflow)
*Goes away with acclimatization

33
Q

How are neurocognitive functions affected by altitude?

A

For the same person at SL vs HA:
Reaction time is increase at HA vs SL
Accuracy is decreased at HA vs SL

  • Coming back from HA, the effects can persist a bit
  • this decrease in cognitive functions is not seen in HA populations
34
Q

How is birth weight affected by living at high altitude?

A

Sea level = highest birth weight, constant until 2000m
Decreases linearly from 2000m → 4550m
4550m = highest altitude/lowest barometric pressure to possibly have a kid

35
Q

How does hemoglobin adapt to altitude?

A

Hb affinity curve straightens / is steeper (more affinity)
*Smaller changes in PO2 required → more release of O2 (dissociation) from Hb
P50 (partial pressure to have 50% saturation) is lower for high altitude living individuals

36
Q

How does Hb affinity adapt to hypoxia?
Compare normoxia vs hypoxia

A

Normoxia:
Prominent metabolic pathway = PPP (pentose phosphate shunt) → to metabolize glucose + membrane bound glycolytic enzymes to BAND3 (PFK/ALD/GAPDH)

Hypoxia:
Deoxygenated Hb → PFK/ALD/GAPDH displaced from BAND3 docking site → promote intracellular glycolysis → increased production of 2,3-BPG → increase P50 (make Hb of lower affinity)

*Seems counterintuitive, but if you are hyperventilating → alkalosis (incrase in pH, reduction in CO2) → affinity of Hb increased
So increasing 2,3-BPG counter keeps balance of Hb affinity

37
Q

What properties of hemoglobin favour respiration?

A

Increases affinity of Hb for oxygen:
- Oxygen itself (cooperativity)
- CO
- Fetal Hb (allosteric Ser for His substitution)

Decreases affinity of Hb for oxygen:
- H+ (allosteric)
- CO2 (allosteric)
- Bisphosphoglycerate (allosteric) - BPG

*Hb always does the right thing → responds to different environments:
In the lungs → high O2, low H+, CO2 → increased affinity → more pick up of O2 by Hb, more dropping off H+ and CO2

In the capillaries → high H+ and CO2, low O2 → Hb responds by picking H+ and CO2, dropping off O2

38
Q

What is polycythemia? How is it related to altitude?

A

Polycythemia = increase in RBC mass

Hypoxia → EPO → polycythemia (over several weeks) → increases viscosity → increases cardiac work → can reduce capacity to exercise

At altitude → allow increased amount of O2 carried even if less O2 saturation

39
Q

What physiological effect is moutain sickness associated with?

A

Associated with excessive erythropoiesis > 21g/dl in men, > 19 g/dl in women
(associated with excess EPO levels in plasma)

Associated with decreased cEpoR (soluble EPO receptor) → binds to EPO → neutralizes it

*bad balance between EPO and receptor

40
Q

How if hemoglobin affinity associated with exercise capacity?

A
  1. P50 and Hb concentration not really related:
    Slightly reduced P50 of high altitude subjects does not enhance gas exchange, impari oxugen extraction or affect peak exercise capacity
  2. P50 is not related to VO2 max (no correlation between P50 and ability to exercise)
  3. Oxygen saturation at peak exercise is correlated with P50
41
Q

What is different about the physiology of Sherpas?
About pH, CO2, Hb, HR

A
  • Reduced sensitivity to hypoxia compared to lowlanders
  • Lower pH in the blood and CSF
  • Higher pCO2 in the blood
  • Hemoglobin levels are higher than lowlanders, but lower than adapted lowlanders
  • Arterial pH during exercise was less alkaline (more H+ ions, more acidic, lower pH)
  • HR reached predicted max during exercise
42
Q

How is the muscle metabolism of Sherpa adapted to altitude?

A

Genetic variants of hypoxia inducible factor (HIF1a)

In skeletal muscle compared to adapted lowlanders:
- lower fatty acid oxidation (more carbs metabolized)
- improved mitochondrial coupling
- protection against oxidative stress

43
Q

What are possible complications of quick ascent to high altitude?

A

Acute moutain sickness → headache, anorexia, insomnia (with periodic breathing), breathlessness, more frequent in younger people

High altitude pulmonary edema → breathlessness, cough with sputum (blood), cyanosis, midl fever (can be life threatening)

High altitude cerebral edema → headache, cerebellar ataxia, irrationality, retinal hemorrhages, papilledema (life threatening)

Treatement for all = descent to lower altitudes (also possible pharmacological therapies)

44
Q

What are the manifestations, risk factors and symptoms of mountain sickness terminate in? How frequent is it?

A

CMS is observed in 5-33% of permanent residents of HA

Diagnosis based on elevated hemoglobin concentration (>21 men, > 19 women)

Symptoms = breathlessness, palpitations, sleep disturbances, cyanosis, dilatation of veins, parenthesis, headaches, tinnitus

Manifestations = Pulmonary hypertension, excess erythrocytosis, cor pulmonale (right heart failure)

Risk factors = genetic predisposition, loss of hypoxic drives
*CMS → High hematocrit / Low ventilation

45
Q

How much are cabines pressurized in commercial flights?

A

Pressurized to equivalent of 1800m - 2500m

Can lead to mild symptoms of acute moutain sickness (ex: periodic breathing), mostly for individuals with baseline hypoxemia (may need supplemental oxygen

Normally decrease in PaO2 stays in flat curve of Hb dissociation curve → no symptoms

PHGY 312 (14 decks)

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